The long-term goal of this project remains the attainment of an atomic- level structure of the human fibrinogen molecule and the elucidation of the interactions that occur during its transformation into fibrin clots. To this end, we are proposing to solve the X-ray structures of several major fragments of human fibrinogen, beginning with fragment D, and then continuing on to the factor XIII-crosslinked moiety known as D-dimer, then fragment E, the complex "D2E", and finally, some small fibrinogens from other creatures. We have already collected data from the crystals of fragment D at a resolution of 3.5 A and have several promising isomorphous heavy metal derivatives in hand. We are currently trying to phase the data and determine an interpretable electron density map. We also have crystals of fragment D complexed with Gly-Pro-Arg-Pro-amide. Significantly, these are in a different space group from the (free) D and have a different unit cell. The unit cell is so large that we may have to collect data from these crystals at a synchrotron facility. We plan to solve the structure by molecular replacement once the (free) D structure is known. We also have the D-dimer crystals in hand. All of these studies should reveal many details of fibrinogen structure and how the molecules interact in the early steps of fibrin formation. The structural basis of genetically defective human fibrinogens will also be clarified. We also plan to continue our longstanding study on peptide antipolymerants, better designs being possible in the light of the determined structures. Finally, there are evolutionary connections between these structures and other proteins (e.g., tenascin) that we plan to exploit.